PAN-811 Inhibits Oxidative Stress-Induced Cell Death of Human Alzheimer's Disease-Derived and Age-Matched Olfactory Neuroepithelial Cells Via Suppression of Intracellular Reactive Oxygen Species

Article type: Research Article

Authors: Nelson, Valery M.^a | Dancik, Chanteé M.^{a; b} | Pan, Weiying^{a; c} | Jiang, Zhi-Gang^{a; *} | Lebowitz, Michael S.^a | Ghanbari, Hossein A.^{a; *}

Affiliations: [a] Panacea Pharmaceuticals, Inc., Gaithersburg, MD, USA | [b] Current address: GeneDx, Gaithersburg, MD, USA | [c] Current address: Johns Hopkins Medicine, Baltimore, MD, USA

Correspondence: [*] Corresponding author: Zhi-Gang Jiang, M.D., Ph.D., Panacea Pharmaceuticals, Inc., 207 Perry Parkway, Suite 2, Gaithersburg, Maryland 20877, USA. Tel.: +1 240 454 8023; Fax: +1 240 465 0650; E-mail: zgjiang@panaceapharma.com; or Hossein A. Ghanbari, Tel.: +1 240 454 8019; Fax: +1 240 465 0450; E-mail: hag@panaceapharma.com.

Abstract: Oxidative stress plays a significant role in neurotoxicity associated with a variety of neurodegenerative diseases including Alzheimer's disease (AD). Increased oxidative stress has been shown to be a prominent and early feature of vulnerable neurons in AD. Olfactory neuroepithelial cells are affected at an early stage. Exposure to oxidative stress induces the accumulation of intracellular reactive oxygen species (ROS), which in turn causes cell damage in the form of protein, lipid, and DNA oxidations. Elevated ROS levels are also associated with increased deposition of amyloid-β and formation of senile plaques, a hallmark of the AD brain. If enhanced ROS exceeds the basal level of cellular protective mechanisms, oxidative damage and cell death will result. Therefore, substances that can reduce oxidative stress are sought as potential drug candidates for treatment or preventative therapy of neurodegenerative diseases such as AD. PAN-811, also known as 3-aminopyridine-2-carboxaldehyde thiosemicarbazone or Triapine, is a small lipophilic compound that is currently being investigated in several Phase II clinical trials for cancer therapy due to its inhibition of ribonucleotide reductase activity. Here we show PAN-811 to be effective in preventing or reducing ROS accumulation and the resulting oxidative damages in both AD-derived and age-matched olfactory neuroepithelial cells.

Keywords: Alzheimer's disease, neuroprotection, olfactory neuroepithelium (ON), oxidative stress, PAN-811

DOI: 10.3233/JAD-2009-1078

Journal: Journal of Alzheimer's Disease, vol. 17, no. 3, pp. 611-619, 2009